DESCRIPTION (Applicant's Description): The candidate, Dr. David Gius, will be an instructor in the Department of Radiation Oncology at Washington University, St Louis, with significant clinical and basic science experience, who seeks additional training in the molecular biology of cell cycle regulation. Dr. Gius will begin working on the mechanisms of programmed cell death, apoptosis, that use cellular pathways independent of tumor suppressor gene p53. While p53 is a central target inducing apoptosis following chemotherapeutic or ionizing radiation, most human malignancies lack a functional p53 protein. Therefore, a model system to study apoptosis in a p53 independent manner, perhaps involving other cell cycle checkpoint target(s), presents the opportunity to study apoptosis in an oncologically relevant manner. T-cell receptor (TCR) activation-induced apoptosis is a unique apoptotic pathway that normally eliminates deleterious T-cell clones in the functional development of the immune system. Strong activation of the TCR in actively dividing T-cells results in a rapid and specific apoptotic death that functions in a p53 independent manner. This model system will be used to gain new insight into the general principles of p53-independent apoptosis and identify potential targets leading to new therapeutic strategies. Ultimately, Dr. Gius wishes to join the faculty at Washington University, where he will apply these studies toward improving the treatment of human malignancies with ionizing radiation. The funds provided by this award are instrumental in allowing Dr. Gius to achieve these goals.